(i) Field of the Invention
The present invention relates to an improved process for the preparation of a mineral acid salt of an amino acid methyl ester and the isolation thereof from the esterification reaction solution in which it is produced. More specifically, it relates to a process for efficiently isolating in high yield a mineral acid salt of an amino acid methyl ester which contains a lesser amounts of impurities such as methanol, water and amino acid from the esterification of an amino acid with methanol in methanol in the presence of a mineral acid
Mineral acid salts of the amino acid methyl esters are important as intermediates in the synthesis of peptides, for example, aspartame, a dipeptide sweetener, and medicines.
(ii) Description of the Prior Art
The esterification of amino acids is known from long ago and fundamentally the process developed by Curtius et al. is still used commercially even today. This process comprises first saturating, with hydrogen chloride, methanol in which an amino acid is dispersed and then, after the reaction is complete, removing excess methanol therefrom, adding fresh methanol thereto so as to increase the concentration of a reaction products, repeating these steps, afterward dehydrating the reaction solution, and finally crystallizing the product using ether or petroleum ether to obtain the desired product. However, this procedure has the deficiencies that in order to remove water formed during the reaction from the system, a great deal of the alcohol is consumed, and what is worse, hydrolysis proceeds in the course of the repeated concentration step. As a result, the yield of the esterified product which is obtained after filtration and drying is at most 90% or so. In addition, if the amino acid produced by the hydrolysis is present in a substantial amount in the thus-produced mineral acid salt, the separation of the desired product from the impurities becomes difficult.
Moreover, because the ether is difficult to handle and recover, its use for the crystallization in the above-described process is not industrially practical.
Another process is also known which comprises first heating an amino acid together with p-toluenesulfonic acid, ethanol and carbon tetrachloride, and then removing the thus-formed water as a azeotropic mixture from the system, whereby a product is obtained as a p-toluene sulfonate salt of an amino acid ethyl ester (Nikkashi, 83, p. 1151, 1962). However, in this process, a nonvolatile acid is required, which is not readily removed from the reaction product, and when methanol is used as the alcohol, a large amount of methanol is consumed, because methanol is removed together with carbon tetrachloride from the system as an azeotropic mixture. Thus, this process is also impractical from an industrial viewpoint.
In Japanese Patent Laid-open No. 165,560/1989, an esterification process is disclosed which comprises reacting an amino acid with an alcohol to prepare an amino acid ester, while the water formed during the reaction is distilled off with the alcohol out of the system. However, this process requires a large amount of the alcohol to remove the water, as in the abovementioned conventional technique, and it also has the drawback that its efficiency is very poor.
In these techniques, after esterification, the crystals can be deposited and separated by filtration, but the filter cake contains water formed during the reaction and a good deal of methanol. If the amino acid ester containing water and the alcohol is directly used as a reaction starting material, the results of reaction are often adversely affected. Therefore, it is an important task to remove the water and the alcohol from the amino acid ester before it is used as a starting material. However if an attempt is made to completely remove water and the alcohol from the reaction mixture by heating, a prolonged operation at a high temperature is required, which causes hydrolysis of the ester and racemization of the amino acid methyl ester occur. Consequently, it is required that the isolation/purification operation is carried out under moderate conditions, which leads to a poor efficiency and a low yield. For this reason, the above-mentioned conventional techniques are industrially unsatisfactory.